Preparation of 14-hydroxycodeinone sulfate

ABSTRACT

Synthetic methods are provided for preparation of oxycodone and salts thereof with an improved impurity profile. Thebaine is converted to 14-hydroxycodeinone sulfate intermediate to minimize a 7,8-dihydro-8,14-dihydroxycodeinone impurity. Efficient methods for conversion of oxycodone base to oxycodone hydrochloride are provided to minimize 14-hydroxycodeinone impurity in the final product.

RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 14/132,825, filed Dec. 18, 2013, which is herein incorporatedby reference in its entirety.

FIELD

Synthetic methods are provided for preparation of 14-hydroxycodeinonesulfate and its use for synthesis of oxycodone and salts thereof withimproved impurity profiles.

DESCRIPTION OF THE RELATED ART

Oxycodone hydrochloride is an opioid receptor agonist that is indicatedfor relief of moderate to severe pain. Preparation of oxycodonehydrochloride from thebaine through intermediate preparation of14-hydroxycodeinine is a well-known technology that has been employedsince 1916.

FIG. 1 shows a prior art conventional synthetic route for preparation ofoxycodone hydrochloride by oxidation of thebaine to form14-hydroxycodeinone (ABUK), reduction of 14-hydroxycodeinone to formoxycodone base, and conversion of the base to oxycodone hydrochloride. Asynthetic impurity, 7,8-dihydro-8,14-dihydroxycodeinone, (DHC),interconverts by hydration/dehydration from/to 14-hydroxycodeinone.Conventional conversion methods to form oxycodone HCl from oxycodonebase using aqueous HCl at elevated temperatures (40-100° C.), or underreflux conditions, can cause acid catalyzed dehydration of residual DHCimpurity to form undesirable ABUK in the final product.

However, the FDA purity requirements for oxycodone hydrochloride havebeen increased, requiring 14-hydroxycodeinine levels to be less than 10ppm or 0.001% in the final product. Improved synthetic methodology toprovide oxycodone hydrochloride of sufficient purity is desirable.

SUMMARY

Synthetic methods are provided for preparation of oxycodonehydrochloride with an improved impurity profile. Thebaine is convertedto 14-hydroxycodeinone sulfate intermediate to minimize a7,8-dihydro-8,14-dihydroxycodeinone impurity. Efficient methods forconversion of oxycodone base to oxycodone hydrochloride are provided tominimize 14-hydroxycodeinone impurity in the final product.

In some embodiments, a method is provided for preparation of oxycodonecomprising exposing thebaine to hydrogen peroxide or peroxyacid andanother organic acid in the presence of sodium hydrogen sulfate, sodiumsulfate, potassium sulfate, potassium hydrogen sulfate and/or sulfuricacid in an aqueous reaction mixture to form 14-hydroxycodeinone sulfate;reducing the 14-hydroxycodeinone sulfate in the presence of a catalystto form oxycodone base; and dissolving the oxycodone base in an aqueousorganic acid to form an oxycodone organic acid salt. In someembodiments, the oxycodone organic acid salt is converted to oxycodonehydrochloride by adding hydrochloric acid or ammonium chloride to theoxycodone organic acid salt to form oxycodone hydrochloride. In someembodiments, the sodium hydrogen sulfate, sodium sulfate, potassiumsulfate and/or potassium hydrogen sulfate is added to the aqueousreaction mixture prior to addition of the hydrogen peroxide orperoxyacid. In some embodiments, the another organic acid is formicacid. In some embodiments, the oxycodone organic acid salt is oxycodoneacetate.

In some embodiments, a method is provided for preparing oxycodonecomprising exposing thebaine to hydrogen peroxide or peroxyacid andanother organic acid in the presence of sodium hydrogen sulfate, sodiumsulfate, potassium sulfate, potassium hydrogen sulfate and/or sulfuricacid in an aqueous reaction mixture to form 14-hydroxycodeinone sulfate;reducing the 14-hydroxycodeinone sulfate in the presence of a catalystto form oxycodone base; and dissolving the oxycodone base in an aqueousorganic acid to form an oxycodone organic acid salt. In someembodiments, the method further comprises adding hydrochloric acid orammonium chloride to the oxycodone organic acid salt to form oxycodonehydrochloride, wherein any 8,14-dihydroxy-7,8-dihydrocodeinone impuritypresent in the oxycodone base is not converted to 14-hydroxycodeinone.

In some embodiments, a method is provided for preparation of oxycodonehydrochloride comprising oxidizing thebaine to provide14-hydroxycodeinone sulfate and further comprising isolating the14-hydroxycodeinone sulfate from the aqueous reaction mixture to formisolated 14-hydroxycodeinone sulfate or a hydrate thereof. In someembodiments, the 14-hydroxycodeinone sulfate hydrate is selected from ahemihydrate, monohydrate, sesquihydrate, or dihydrate.

In some embodiments, a method is provided for providing oxycodonehydrochloride comprising reducing the isolated 14-hydroxycodeinonesulfate or a hydrate thereof in the presence of the catalyst to formoxycodone base. In some embodiments, the oxycodone base is purified toform purified oxycodone base. In some embodiments, the purifiedoxycodone base has not more than 0.10%, 0.05%, or 0.01% of a8,14-dihydroxy-7,8-dihydrocodeinone (DHC, DHDHC) impurity.

In some embodiments, a method is provided for converting oxycodone baseto oxycodone hydrochloride comprising dissolving oxycodone base in anaqueous organic acid. In some embodiments, the dissolving comprisescomplete or partial dissolution of the oxycodone base in the aqueousorganic acid. In some embodiments, the aqueous organic acid is aqueousacetic acid. In some embodiments, the dissolving step is performed at atemperature within the range from about 0° C. to about 70° C.; about 0°C. to about 60° C.; about 0° C. to about 50° C.; or about 10° C. to 40°C.; or at ambient temperature. In some embodiments, the purifiedoxycodone hydrochloride has not more than 0.15%, 0.10%, 0.05%, or 0.01%of an 8,14-dihydroxy-7,8-dihydrocodeinone (DHC) impurity.

In some embodiments, methods comprise purifying the oxycodonehydrochloride by a method comprising crystallizing the oxycodonehydrochloride to form purified oxycodone hydrochloride. In someembodiments, the crystallizing is performed by addition of water and/orone or more water miscible organic solvents to the oxycodonehydrochloride to form the purified oxycodone hydrochloride. In someembodiments, the crystallizing is performed at a temperature rangewithin about 0° C. to about 30° C.; or from about 5° C. to about 15° C.

In some embodiments, methods are provided for purifying oxycodonehydrochloride comprising crystallizing to form purified oxycodonehydrochloride from water or a combination of water and one or more watermiscible organic solvents selected from the group consisting ofisopropyl alcohol, ethanol, methanol, methyl ethyl ketone and acetone.In some embodiments, the purified oxycodone hydrochloride has less than0.01% 14-hydroxycodeinone; less than 0.001% 14-hydroxycodeinone; lessthan 0.0005% 14-hydroxycodeinone; or less than 0.0002%14-hydroxycodeinone.

In some embodiments, the thebaine starting material is selected orobtained from concentrated poppy straw, anhydrous or raw thebainealkaloid. In some embodiments, thebaine starting material is obtainedfrom a commercial and/or synthetic source.

In some embodiments, a method is provided for preparation of14-hydroxycodeinone sulfate or a hydrate thereof comprising exposingthebaine to hydrogen peroxide or peroxyacid and another organic acid inthe presence of sodium hydrogen sulfate, sodium sulfate, potassiumsulfate, potassium hydrogen sulfate and/or sulfuric acid in an aqueousreaction mixture; and isolating a precipitate of 14-hydroxycodeinonesulfate or a hydrate thereof from the reaction mixture. In someembodiments, the another organic acid is formic acid. In someembodiments, the 14-hydroxycodeinone sulfate has less than 0.05%,0.025%, or 0.01% of DHC impurity.

In some embodiments, methods are provided for purifying14-hydroxycodeinone sulfate by a method comprising recrystallizationfrom an aqueous solvent.

In some embodiments, a compound is provided comprising14-hydroxycodeinone sulfate or a hydrate thereof. The isolated14-hydroxycodeinone sulfate hydrate is a 14-hydroxycodeinone sulfatehemihydrate, monohydrate, sesquihydrate or dihydrate.14-hydroxycodeinone hemisulfate monohydrate is provided.

In some embodiments, the isolated 14-hydroxycodeinone sulfate or hydratethereof exhibits not more than 0.05%, 0.025%, or 0.01% DHC impuritylevel.

In some embodiments, a method is provided for preparation of oxycodonebase from 14-hydroxycodeinone sulfate or a hydrate thereof comprisingreducing the 14-hydroxycodeinone sulfate or hydrate thereof in thepresence of a catalyst to form oxycodone base. In some embodiments, theoxycodone base is purified to form purified oxycodone base.

In some embodiments, a method is provided for preparation of oxycodonehydrochloride from oxycodone base comprising dissolving oxycodone basein an aqueous organic acid; and adding hydrochloric acid or ammoniumchloride to the solution to form oxycodone hydrochloride. In someembodiments, the dissolving comprises complete or partial dissolution ofthe oxycodone base in the aqueous organic acid. In some embodiments, theaqueous organic acid is selected from tartaric acid, fumaric acid,trifluoroacetic acid, trichloroacetic acid, monochloroacetic acid,lactic acid, glycolic acid, and acetic acid. In some embodiments, theaqueous organic acid is aqueous acetic acid.

In some embodiments, the oxycodone hydrochloride is crystallized byadding water and/or one or more water miscible organic solvents to theoxycodone hydrochloride to form purified oxycodone hydrochloride. Insome embodiments, the crystallizing is performed at a temperature rangewithin about 0° C. to about 30° C.; or at a temperature range of fromabout 5° C. to about 35° C.

In some embodiments, a method is provided for preparation of oxycodonebase comprising treating 14-hydroxycodeinone sulfate or a hydratethereof with calcium acetate or barium acetate to prepare a14-hydroxycodeinone acetate solution; and reducing the14-hydroxycodeinone acetate solution to form oxycodone base.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a prior art conventional synthetic route for preparation ofoxycodone hydrochloride by oxidation of thebaine to form14-hydroxycodeinone (ABUK), reduction of 14-hydroxycodeinone to formoxycodone base, and conversion of the base to oxycodone hydrochloride. Asynthetic impurity, 7,8-dihydro-8,14-dihydroxycodeinone, (DHC),interconverts by hydration/dehydration from/to 14-hydroxycodeinone.Conventional conversion methods to form oxycodone HCl from oxycodonebase using aqueous HCl at elevated temperatures (40-100° C.), or underreflux conditions, can cause acid catalyzed dehydration of residual DHCimpurity to form undesirable ABUK in the final product.

FIG. 2 shows a synthetic route for preparation of 14-hydroxycodeinonesulfate by oxidation of thebaine and treatment with sodium hydrogensulfate.

FIG. 3 shows a synthetic route for preparation of 14-hydroxycodeinonesulfate by oxidation of thebaine and treatment with potassium hydrogensulfate.

FIG. 4 shows a method for purification of impure 14-hydroxycodeinonesulfate by neutralization to form ABUK base, then dissolution of thebase in aqueous acetic acid and crystallization of 14-hydroxycodeinoneas a sulfate salt.

FIG. 5 shows a synthetic route for preparation of oxycodone base fromreduction of 14-hydroxycodeinone sulfate with formic acid overPd/C-catalyst.

FIG. 6 shows methods for preparing oxycodone hydrochloride from14-hydroxycodeinone sulfate.

FIG. 7 shows two methods for conversion of oxycodone base to oxycodonehydrochloride via oxycodone acetate and either HCl or ammonium chloride.

FIG. 8 shows a synthetic route for conversion of oxycodone base tooxycodone hydrochloride.

FIG. 9 shows preparation of ABUK solution in acetic acid andhydrogenation to form oxycodone acetate.

FIG. 10 shows ¹H NMR Spectrum of 14-hydroxycodeinone base.

FIG. 11 shows a ¹³C NMR Spectrum of 14-hydroxycodeinone base.

DETAILED DESCRIPTION

Oxycodone hydrochloride is an opioid agonist compound that is valuableas an active pharmaceutical ingredient (API) and as a starting materialin the preparation of the opioid antagonists naloxone and naltrexone.Preparation of oxycodone hydrochloride from thebaine throughintermediate preparation of 14-hydroxycodeinine is a well-knowntechnology that has been known since 1916. For example, oxidation ofthebaine provides intermediate 14-hydroxycodeinone (α,β unsaturatedketone, ABUK), followed by reduction of the ABUK to provide oxycodonebase, and finally conversion of oxycodone base provides oxycodonehydrochloride. However, depending on the reagents and reactionconditions employed, various impurities are formed.

As used herein, unless otherwise specified, the term “ABUK”, refers to14-hydroxycodeinone.

During the oxidation of thebaine to give 14-hydroxycodeinone, certainhydrated 14-hydroxycodeinone products can be formed, including8,14-dihydroxy-7,8-dihydrocodeinone (DHC). The DHC impurity can becarried though the process to the production of oxycodone base. Duringconversion of oxycodone free base to oxycodone hydrochloride usingaqueous hydrochloric acid and heat, the DHC impurity can undergoacid-catalyzed dehydration to be converted into 14-hydroxycodeinone(ABUK). Thus, DHC in oxycodone base can be a source of undesirable ABUKimpurity in the final oxycodone hydrochloride. In addition, 6-oxycodolimpurities (6α- and/or 6β-oxycodol isomers) can be present in oxycodonebase, for example, due to over-reduction of ABUK. In some embodiments,the term oxycodol refers to 6-oxycodol (both 6α- and 6β-oxycodolisomers). In some embodiments, the term 6-oxycodol major isomer refersto 6α-oxycodol.

Synthetic methods that minimize the presence of each of the impuritiesin final product are desirable. The structures of oxycodone and theimpurities oxycodol (2 isomers), DHC, and ABUK are shown in Scheme 1.

The United States Food and Drug Administration (FDA) has been requestingfor over ten years that manufacturers of oxycodone hydrochloride activepharmaceutical ingredient (API) to reduce levels of the impurity14-hydroxycodeinone in their products. Since at least 2010, the FDA hasrequired that sponsors seeking to market certain oxycodone products useoxycodone hydrochloride API containing not more than 10 parts permillion (0.001%) of 14-hydroxycodeinone, or submit data adequatelyqualifying the impurity for safety.

High ABUK content in oxycodone hydrochloride API can be explained by (1)insufficient reduction of ABUK (product-intermediate of the firstsynthetic step) to oxycodone base (OC-base) or (2) by conversion ofresidual amount of the impurity DHC in oxycodone base into ABUK, forexample, by acid catalyzed dehydration, during the last step ofoxycodone hydrochloride preparation.

Improved methods for commercial synthesis are desirable in order toreduce the impurity profile of oxycodone hydrochloride.

Many of the known 14-hydroxycodeinone (ABUK) preparation proceduresprovide a preparation of ABUK in the form of ABUK formate salt solutionin the aqueous reaction mixture. To separate ABUK from other reactants,side-reaction products, tar and so on, the reaction mixture in thesecases is conventionally treated with ammonium or potassium or sodiumhydroxides inducing the ABUK base precipitation. Such isolated ABUK basehas elevated DHC level (up to 0.5-2.0%) and its further usage as astarting material for the oxycodone preparation is not acceptablebecause elevated DHC levels in the ABUK base can lead to a high level ofABUK impurity in the final oxycodone hydrochloride product understandard reaction conditions.

In some embodiments, methods are provided herein for conversion ofthebaine to 14-hydroxycodeinone sulfate (ABUK sulfate) with minimalformation of the impurity DHC (0-250 ppm), and other impurities, at aconversion rate greater than 99%. In some embodiments, methods areprovided for minimizing the amount of DHC in ABUK syntheticintermediate. In some embodiments, pure 14-hydroxycodeinone sulfateintermediate is converted to oxycodone base using a two-stage reductionthat minimizes residual ABUK sulfate to undetectable levels; remarkablywithout significant formation of DHC or other impurities. In someembodiments, the ABUK sulfate is reduced directly to oxycodone withoutbeing converted back to its base form. In some embodiments, methods areprovided to minimize production and/or presence of oxycodol and otherimpurities in the oxycodone base. In some embodiments, the disclosureprovides methods for preparing oxycodone hydrochloride from oxycodonebase without conversion of DHC to ABUK on the final step.

In some embodiments, methods are provided for preparation of oxycodonehydrochloride that minimize or eliminate detectable DHC in oxycodonebase.

In some embodiments, methods for converting oxycodone base to oxycodonehydrochloride are provided that minimize or eliminate acid catalyzeddehydration of DHC to ABUK. In some embodiments, methods are providedfor converting oxycodone base to oxycodone hydrochloride that minimizeacid-catalyzed dehydration of DHC to ABUK comprising dissolving theoxycodone base in an organic acid and water without heating prior tointroduction of hydrochloric acid. In some embodiments, methods areprovided for converting oxycodone base to oxycodone hydrochloride thatminimize acid-catalyzed dehydration of DHC to ABUK comprising dissolvingthe oxycodone base in an organic acid and water at ambient temperatureprior to introduction of hydrochloric acid. In some embodiments, theorganic acid is selected from tartaric acid, fumaric acid, lactic acid,trifluoroacetic acid, trichloroacetic acid, monochloroacetic acid,glycolic acid, and acetic acid. In some embodiments, the oxycodone baseis dissolved or partially dissolved in organic acid and water, whereinthe organic acid is acetic acid, prior to the introduction of HCl forthe conversion of oxycodone base to oxycodone HCl, as shown in FIG. 8.

In some embodiments, synthetic methods are provided for the productionof highly pure oxycodone hydrochloride API. In some embodiments, theoverall process follows four main steps. An outline of the overallprocess comprising three or four main steps:

-   -   1. Oxidation of CPS-ATA to form 14-Hydroxycodeinone Sulfate        (ABUK sulfate);    -   2. Reduction of 14-Hydroxycodeinone Sulfate to crude Oxycodone        base;    -   3. Purification of Crude Oxycodone Base (optional); and    -   4. Preparation of Oxycodone Hydrochloride and its        Crystallization.

Step 1: Oxidation of CPS-ATA to Form 14-Hydroxycodeinone Sulfate.

In some embodiments, methods are provided to minimize the amount of DHCimpurity in the 14-hydroxycodeinone (ABUK) intermediate. In someembodiments, DHC formation is minimized by preparing the ABUKintermediate as a sulfate salt. In other embodiments, the DHC impurityis further minimized by purification and/or isolation of the14-hydroxycodeinone sulfate salt. The DHC impurity is undesirablebecause it can be carried through the process and be converted to ABUKin conventional preparation of oxycodone hydrochloride.

In embodiments, methods are provided for ABUK preparation as an ABUKsulfate salt form. In some embodiments, the ABUK sulfate is isolated. Insome embodiments, the ABUK sulfate is isolated as a hydrate. In someembodiments, the ABUK sulfate is isolated in an anhydrous form. In someembodiments, the ABUK sulfate is isolated as a hemihydrate, monohydrate,sesquihydrate or dihydrate. In specific embodiments, the ABUK sulfate isABUK×0.5H₂SO₄×2H₂O (MW 398.42). In some embodiments, the ABUK sulfateform has not more than 300 ppm, not more than 150 ppm, not more than 100ppm, not more than 75 ppm, not more than 50 ppm, not more than 25 ppm,or not more than 10 ppm of an 8,14-dihydroxy-7,8-dihydrocodeinone (DHC)impurity. In many instances, DHC was not detectable in ABUK preparationsaccording to the methods provided herein.

In some embodiments, the 14-hydroxycodeinone sulfate is purified by anaqueous treatment and recrystallization. In some embodiments, the ABUKsulfate is re-crystallized from water. In one experiment,recrystallization of impure ABUK sulfate (213 ppm DHC) from waterprovided ABUK sulfate with 24 ppm DHC in an 81% yield.

Methods are provided for the preparation of oxycodone hydrochloride froma thebaine component selected from synthetic thebaine, concentratedpoppy straw, anhydrous or raw thebaine alkaloid (CPS-ATA), or thebainefrom various other sources. Thebaine component can be obtained from acommercial source and used directly or further isolated and/or purifiedprior to use. Thebaine (paramorphine) can be obtained from opium poppiesor related species including various strains of Papaver somniferum, P.orientale or P. bracteatum plants, for example, leaves, roots, pedicels,straw, chaff, head, pod, capsules, seeds or bled latex. Various methodsfor production of thebaine are known in the art, for example, U.S. Pat.No. 6,723,894 which is incorporated herein by reference. Various routesfor the synthesis of thebaine are known, for example, U.S. Pat. Nos.4,613,668; 4,795,813; 8,067,597, each of which is incorporated herein byreference.

In some embodiments, thebaine starting material is selected from anycommercial or synthetic source. In some embodiments, poppy straw orconcentrated poppy straw rich in thebaine (CPS-ATA) is employed as aneconomical source of thebaine component. In some embodiments, thethebaine component is CPS-ATA. In some embodiments, CPA-ATA is useddirectly as the thebaine component.

In some embodiments, methods are provided for preparation of14-hydroxycodeinone (ABUK) sulfate from thebaine component. In someembodiments, thebaine component is, for example, CPS-ATA. In someembodiments, methods are provided for preparation of ABUK sulfatecomprising mixing thebaine component, water, sodium hydrogen sulfate,formic acid and 30% hydrogen peroxide aqueous solution, and stirring ofthe prepared mixture at a temperature within the range of from about50-80° C. until a complete conversion of thebaine into ABUK is detected.In some embodiments, the oxidation reaction is monitored by HPLC. Thevisible sign of the reaction progress is a massive precipitation of ABUKsulfate from the reaction mixture. At the end of the reaction, anadditional amount of water is added for the proper crystallization ofthe reaction product at ambient temperature. The reaction product isisolated by filtering off precipitated solid material, and productwashing with water and acetone mixture, water or ammonium sulfateaqueous solution; followed by drying on filter. The typical yieldfollowing washing with acetone/water mixture, for example, 3/1 acetonewater, is within the range of from about 70-75% of pure product.

In some embodiments, the method for preparing ABUK sulfate from thebainecomponent comprises washing wet ABUK sulfate product with ammoniumsulfate aqueous solution to prevent ABUK sulfate losses on washings. Insome embodiments, cold 40% ammonium sulfate aqueous solution is used inthe washing step. In some embodiments, ABUK sulfate product washing onfilter with 40% ammonium sulfate aqueous solution ((NH₄)₂SO₄) isemployed to increase yield to about 75-80% and prevent product lossesdue to its high solubility in water or aqueous organic solvents, such asacetone/water mixtures. Although some sulfate salts such as ammonium andsodium sulfate can be present in a minor amount in the ABUK sulfateproduct, the product is suitable for catalytic reduction for thepreparation of oxycodone base.

The filtrate contains impure ABUK, DHC, salts, colored materials andother impurities. In some embodiments, methods for isolation of purifiedABUK sulfate from this filtrate are provided. Example 1 provides arepresentative 30-g scale oxidation process run at 60° C., for less than6 hours for production of 14-hydroxycodeinone sulfate from thebaine.

In some embodiments, methods are provided for purifying ABUK sulfate.Impure ABUK sulfate intermediate batches can be recycled by this processby neutralization with ammonium hydroxide of mother liquors of either anaqueous solution or impure ABUK sulfate intermediate batches. As shownin FIG. 4, the impure ABUK base can be purified using thecrystallization of ABUK in form of sulfate salt that can be used for theoxycodone preparation.

In some embodiments, a method is provided for purifying oxycodone basecomprising dissolving impure ABUK base in aqueous acetic acid, treatingthe solution with sulfate anion sources (sulfuric acid, sodium sulfate,sodium or potassium hydrogen sulfate), and crystallizing ABUK sulfatefrom the aqueous solution. The crystallized solids are isolated byfiltering off, washing and drying. In some embodiments, a method forproviding purified ABUK sulfate comprises neutralizing impure ABUKsulfate by addition of water and ammonium hydroxide to provide ABUKbase; dissolving the water insoluble ABUK base in aqueous acetic acid toform ABUK acetate; crystallizing ABUK sulfate from water and sulfuricacid, sodium sulfate or potassium hydrogen sulfate; and isolating thepurified ABUK sulfate.

Step 2: Reduction of 14-Hydroxycodeinone Sulfate to Crude OxycodoneBase.

In some embodiments, methods are provided for preparing crude oxycodonebase with a minimal amount of ABUK and DHC to prevent ABUK formation onthe last technological step—oxycodone HCl preparation. In someembodiments, the highest limit of ABUK in the final product is set as 10ppm.

Chemically, the reduction step is a catalytical reduction of the ABUKsulfate carbon-carbon double bond with oxycodone formation. In someembodiments, the reduction can employ hydrogen gas or formic acid asreducing agents, as shown in FIG. 3. Catalyst in both cases is apalladium on charcoal (Pd/C) wet catalyst (for example, 10% catalyst,LOD 50%). As a side process, there can be a reduction of ABUK sulfateketo-group and C—C-double to form oxycodol, an impurity in oxycodonehydrochloride. Isomers of oxycodol are shown in Scheme 2.

In case of hydrogen-gas reducing agent, oxycodol can occur in thereaction mixture in amount of about 1.5%. In the case of formic acid asa reducing agent, oxycodol content can be 4 to 6%. In some embodiments,further methods are provided for the isolation and purification ofoxycodone base and/or oxycodone hydrochloride in order to remove asignificant portion of oxycodol impurity. In some embodiments, the limitof 6α-oxycodol in final oxycodone hydrochloride is set as 0.25% by USPharmacopeia (USP). Therefore, in some embodiments, methods forminimizing oxycodol content in oxycodone base and oxycodonehydrochloride are provided.

In some embodiments, methods are provided for reducing14-hydroxycodeinone to oxycodone with minimal impurities, comprisingmixing ABUK sulfate in water; reducing the ABUK sulfate with a catalystand either hydrogen or a hydrogen transfer reagent; filtering off thecatalyst with water and/or aqueous acetic acid; neutralizing to basic pHto form oxycodone base; and isolating the oxycodone base. In someembodiments, the pH is adjusted with ammonium hydroxide. In someembodiments, the pH is adjusted with ammonium hydroxide to from about pH8.0 to about pH 10.5; or from about pH 8.5 to about pH 10.0. In someembodiments, the pH is adjusted with ammonium hydroxide to about pH 9.5.

In some embodiments, the mixing step and/or reducing steps are performedunder nitrogen or argon gas.

In some embodiments, the reducing step is performed with a reducingcatalyst selected from the group consisting of palladium on activecarbon (Pd/C), Pd/C/FeCl₃, Pd/C/Fe(III) hydroxide or oxide, Pd/Al₂O₃,Pt/C, Pt/Al₂O₃, Pd/BaSO₄, Raney Ni-catalysts, Urushibara Ni-catalysts,rhodium on active carbon, Raney nickel, ruthenium black, PtO₂, Pt/C andplatinum black. In some embodiments, the reducing catalyst is selectedfrom 1-20% palladium on active carbon (Pd/C), Pd/C/FeCl₃, Pd/C/Fe(III)hydroxide or oxide; 0.04-10% Pd/Al₂O₃, 5% Pt/C, 5% Pt/Al₂O₃, or 5%rhodium on active carbon. In specific embodiments, the reducing step isperformed with a palladium on carbon catalyst Pd/C catalyst selectedfrom 2% Pd/C, 2.5% Pd/C, 3% Pd/C, 5% Pd/C, 10% Pd/C, or 5% Pd/BaSO₄.

In some embodiments, the reducing step is performed with a regenerablepalladium, platinum, rhodium, nickel or ruthenium catalyst. In someembodiments, the catalyst may be either dry or in wet form with e.g. 50%water. In some embodiments, the catalyst is 10% Pd/C (50% L.O.D.). Insome embodiments, the reducing catalyst is used in an amount from about0.01-5 wt %, 0.02-3 wt % or 0.03-1.6 wt % with respect to the startingABUK sulfate.

In some embodiments, the reducing step is performed with a reducingcatalyst as described herein and hydrogen. In some embodiments, thereducing step is performed with a reducing catalyst as described hereinand a hydrogen transfer reagent. The hydrogen transfer reagent is usedas a hydrogen donor. The hydrogen donor must correspond to the catalyst,therefore formic acid and hypophosphorous acid as well as the saltsthereof, such as triethylammonium formate, tri-n-butylammonium formate,sodium formate, potassium formate and ammonium formate as well as sodiumhypophosphite are used. In some embodiments, the reducing step employs acatalyst and a hydrogen transfer reagent that is formic acid.

In some embodiments, a method is provided for reducing14-hydroxycodeinone sulfate to oxycodone base comprising exposing14-hydroxycodeinone sulfate to a reducing catalyst and hydrogen and/or ahydrogen transfer agent at a temperature of less than 50° C. In someembodiments, the method is performed at less than 45° C. As demonstratedin the examples, the method for reducing 14-hydroxycodeinone sulfate tooxycodone base, even when performed without acetic acid as a co-solventand without additional reduction treatment of the reaction mixture withformic acid at elevated temperature, surprisingly exhibited highercatalyst selectivity resulting in minimized oxycodol formation in theoxycodone base.

In some embodiments, a method is provided for reducing14-hydroxycodeinone to oxycodone further comprising one or morecatalytic reduction steps. In some embodiments, a method is providedwith an additional catalytical reduction step with formic acid as areducing agent. In some embodiments, the additional catalyticalreduction step is performed without intermediate oxycodone baseisolation. In some embodiments, the additional catalytical reductionstep comprises adding formic acid and additional catalyst to thereaction mixture. In some embodiments, the additional catalyticreduction step is performed at 50-60° C. for about one hour.

In some embodiments, an additional catalytic reduction step is performedwith intermediate oxycodone base isolation. In this case, oxycodonecrude is isolated from the initial reductive system performed withPd/C-catalyst. In this case, the additional reduction method furthercomprises isolating oxycodone base from the reaction mixture by addingammonium hydroxide solution and filtering to obtain initial crudeoxycodone base; converting the initial crude oxycodone base to itsformate salt in aqueous solution and treating with formic acid overPd/C-catalyst at around 50° C. In both cases, good quality crudeoxycodone was prepared.

For example, in experiments with hydrogen gas as a reducing agent suchas Example 13, a magnetically stirred mixture of ABUK sulfate, water,and Pd/C catalyst was purged with inert gas and hydrogen for 5.25 hoursat ambient temperature until 279 ppm ABUK content remained. Formic acidand a fresh portion of Pd/C-catalyst were added to the reaction mixtureand reaction was continued at about 50° C. (usually for 1 hour) and thenthe reaction mixture was cooled down to ambient temperature. In someembodiments, crude oxycodone base is isolated using ammonium hydroxide.

In some embodiments, methods are provided for preparing oxycodoneacetate by conversion of 14-hydroxycodeinone sulfate to oxycodoneacetate, comprising dissolving barium diacetate in aqueous acetic acidto form a solution; adding ABUK sulfate to the solution; filtering thesolution; adding a Pd/C catalyst to the filtrate to form a mixture; andhydrogenating the mixture to provide oxycodone acetate, as shown in FIG.9. In some embodiments, the oxycodone acetate solution is treated with abase to provide oxycodone base. In some embodiments, the oxycodoneacetate is treated with ammonium hydroxide to provide oxycodone base.

Selection of Solvent in Reducing Step.

It has been shown that over-reduction of 14-hydroxycodeinone can lead to6-hydroxy impurities such as 6-oxycodols. For example, Kok andScammells, employed 5% Pd/BaSO₄ or 3% Pd/C as hydrogenation catalystsand performed the reduction of 14-hydroxycodeinone in aqueous aceticacid. In both cases a significant major impurity corresponding to the6-hydroxy analog was formed due to over-reduction. Changing the solventto methanol for reduction of either 14-hydroxycodeinone or14-hydroxycodeinone HCl salt, resulted in a decrease in the formation ofthe 6-hydroxy by-product using either catalyst. See Table 1 in Kok andScammell, RSC Adv. 2012, 2, 11318-11325, which is incorporated herein byreference. In some embodiments, the reduction is performed in a solventselected from one or more of water, acetic acid, aqueous acetic acid,aqueous formic acid, ethanol, or methanol.

Step 3: Purification of Crude Oxycodone Base.

In some embodiments, oxycodone base crude is converted directly intooxycodone hydrochloride. In some embodiments, oxycodone base is purifiedprior to converting to oxycodone hydrochloride. In some embodiments,methods are provided for purifying crude oxycodone base to removeprocess impurities. In some embodiments, oxycodone base is purified by aprocess comprising crystallizing, recrystallizing or triturating thecrude oxycodone base in a solvent. In some embodiments, methods forproducing oxycodone hydrochloride comprise purifying oxycodone base bytreating with an organic solvent. In some embodiments, the organicsolvent is a water-miscible solvent selected from ethanol, acetone orisopropyl alcohol. In some embodiments, the organic solvent is acombination of a halogenated solvent and a water miscible solvent. Insome embodiments, oxycodone base is dissolved in a halogenated solventprior to adding one or more water miscible solvents. In someembodiments, the organic solvent is a combination of a water misciblesolvent with a halogenated solvent, wherein the halogenated solvent isselected from chloroform, or dichloromethane. In some embodiments, thewater miscible solvent is selected from any water miscible solvent knownin the art. In some embodiments, the water miscible solvent is selectedfrom one or more of methanol, ethanol, isopropyl alcohol, methyl ethylketone, acetone, ethylene glycol, propylene glycol, monomethyl- ormonoethyl ethers of ethylene- or propylene glycols. In some embodiments,the organic solvent is selected from methanol or isopropyl alcohol. Insome embodiments, the organic solvent is a mixture of methanol andisopropyl alcohol. In some embodiments, the organic solvent is isopropylalcohol. In some aspects, methods for oxycodone base purification areprovided comprising treating the crude oxycodone base with isopropylalcohol to provide oxycodone base with reduced levels of impurities.

In some embodiments, methods are provided for purifying crude oxycodonebase to remove process impurities comprising crystallizing,recrystallizing or triturating the crude oxycodone base in a solventthat is a mixture of one or more water miscible organic solvents.

In some embodiments, methods are provided for purifying crude oxycodonebase to remove process impurities comprising crystallizing,recrystallizing or triturating the crude oxycodone base in a solventthat is a mixture of water and one or more water miscible organicsolvents in a ratio within from about 5 to 95 vol %, 10 to 70 vol %, 20to 60 vol %, or 30 to 50 vol % with water. In some embodiments, thesolvent for the oxycodone base purification is a mixture of one or morewater miscible organic solvents at about 20 vol %, 30 vol %, 35 vol %,45 vol % or 50 vol % water miscible organic solvents in water.

In some embodiments, a method for purifying oxycodone base comprisestreating oxycodone base with one or more organic solvents, or one ormore organic solvents and water.

In some embodiments, oxycodone base is purified in a water/organicsolvent system to economize on use of organic solvent.

In some aspects, oxycodone base is treated with a mixture of water andisopropyl alcohol; a mixture of water, isopropyl alcohol and propyleneglycol; a mixture of water, isopropyl alcohol and methoxyethanol; or amixture of water, isopropyl alcohol and ethylene glycol. In someaspects, the method comprises treating oxycodone base with a mixture ofwater and isopropyl alcohol in a ratio of about 2:1 (v/v). In someaspects, the method comprises treating oxycodone base with a mixture ofwater/isopropyl alcohol/propylene glycol in a ratio of about 6:2:3(v/v). In some aspects, the method comprises treating oxycodone basewith a mixture of water/isopropyl alcohol/methoxyethanol in a ratio ofabout 6:1:3 (v/v).

In one aspect, a method is provided for purifying crude oxycodone base,the method comprising transferring isolated crude oxycodone base into areaction vessel with isopropyl alcohol; and refluxing the oxycodone basewith isopropyl alcohol to provides crystalline purified oxycodone base.The product is obtained by filtering, rinsing with IPA and drying toprovide purified oxycodone base that is suitable for the oxycodonehydrochloride preparation step.

In another aspect, a method is provided for purifying crude oxycodonebase, the method comprising completely dissolving crude oxycodone basein small volume of chloroform or chloroform/methanol mixture; dilutingthe mixture with isopropyl alcohol to form a homogenous mixture;distilling off the chloroform under nitrogen and precipitating thecrystalline oxycodone base from isopropyl alcohol. The crystallineoxycodone base is filtered, rinsed with isopropyl alcohol and dried toprovide purified oxycodone base, suitable for the oxycodonehydrochloride preparation step.

In some embodiments, methods are provided for preparing oxycodone basewith not more than 0.25%, 0.20%, 0.15%, 0.10%, 0.05%, or 0.025% DHC. Forexample, oxycodone base crude comprising 0.0202% DHC was obtained byreducing 14-hydroxycodeinone sulfate in water without any purification.

In some embodiments, methods are provided for preparing oxycodone basewith not more than 0.50%, 0.25%, 0.15%, 0.10%, total 6-oxycodol.

In some embodiments, methods are provided for preparing oxycodone basewith not more than 0.1%, 0.010%, 0.005%, 0.002%, or 0.001% (less than 10ppm) ABUK.

Step 4: Preparation and Crystallization of Oxycodone Hydrochloride.

Conventional conversion of oxycodone base to oxycodone HCl using aqueousHCl is typically performed at elevated temperatures, such as at atemperature greater than about 50° C., greater than about 55° C.,greater than about 60° C., or at about 70° C. up to 100° C., or higher.

However, directly converting oxycodone base to oxycodone hydrochloridewith strong acid and elevated temperature conditions may provoke acidcatalyzed dehydration of DHC impurity to ABUK.

In some embodiments, in order to avoid DHC conversion into ABUK at thefinal oxycodone hydrochloride preparation step, methods are providedthat avoid use of both strong acid (HCl) and high temperature.

In some embodiments, methods are provided for minimizing ABUK formationdue to residual DHC in oxycodone base in the last technological step ofoxycodone HCl preparation.

In some embodiments, methods are provided for converting oxycodone baseto oxycodone hydrochloride comprising converting oxycodone base tooxycodone acetate, and exposing the oxycodone acetate to HCl.

In some embodiments, a method is provided for preparation of oxycodonehydrochloride from oxycodone base comprising dissolving oxycodone basein an aqueous organic acid; and adding hydrochloric acid or ammoniumchloride to the solution to form oxycodone hydrochloride. In someembodiments, the dissolving comprises complete or partial dissolution ofthe oxycodone base in the aqueous organic acid. In some embodiments, theaqueous organic acid is selected from tartaric acid, fumaric acid,lactic acid, trifluoroacetic acid, trichloroacetic acid,monochloroacetic acid, glycolic acid, and acetic acid. In someembodiments, the aqueous organic acid is aqueous acetic acid.

In some embodiments, methods are provided for converting oxycodone baseto oxycodone hydrochloride comprising dissolving oxycodone base inaqueous organic acid at a temperature below 50° C., below 40° C., orbelow 30° C., to form an oxycodone organic acid salt in situ, andexposing the oxycodone organic acid salt to HCl or ammonium chloride.

In some embodiments, the oxycodone organic acid salt is oxycodoneacetate.

In some embodiments, methods are provided for converting oxycodone baseto oxycodone hydrochloride comprising dissolving oxycodone base inaqueous acetic acid at a temperature below 50° C., below 40° C., orbelow 30° C., to form oxycodone acetate in situ, and exposing theoxycodone acetate to HCl as shown in FIG. 8.

In some embodiments, the oxycodone acetate is isolated or utilized insitu to form an oxycodone organic acid salt or an oxycodone inorganicacid salt.

In some embodiments, the oxycodone inorganic acid salt is selected fromoxycodone hydrochloride, hydrobromide, hydrofluoride, phosphate,sulfate, or nitrate. In some embodiments, the oxycodone inorganic acidsalt is selected from oxycodone hydrochloride, oxycodone hydrobromide,or oxycodone sulfate. In some embodiments, the oxycodone inorganic acidsalt is oxycodone hydrochloride.

In some embodiments, the oxycodone organic acid salt is selected fromorganic acid salts such as terephthalate, citrate, lactate, glycolate,tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate,trifluoroacetate, oxalate, formate, succinate, and the like; and aminoacid salts such as aspartate, glutamate and the like.

In some embodiments, the oxycodone organic acid salt is oxycodoneacetate or oxycodone terephthalate. In some embodiments, the oxycodoneorganic acid salt is oxycodone acetate.

In some embodiments, methods are provided for preparing oxycodonehydrochloride with not more than 200 ppm (0.02%); 150 ppm (0.015%); 100ppm (0.01%); 75 ppm (0.0075%); 50 ppm (0.005%) or 25 ppm (0.0025%)14-hydroxycodeinone. In some embodiments, oxycodone hydrochloride isprovided with not more than 10 ppm, 5 ppm, 3 ppm, 2 ppm or 1 ppm14-hydroxycodeinone.

FDA guidelines provide a limit of not more than 0.001% of API (10 partsper million (ppm)) as the acceptable level of 14-hydroxycodeinoneimpurity in oxycodone HCl. In some embodiments, methods are provided forpreparing oxycodone HCl with not more than 0.01%, 0.0075%, 0.005%,0.001%, 0.0005%, 0.0003%, 0.0002%, or 0.0001% 14-hydroxycodeinone.

In some embodiments, methods are provided for preparing oxycodonehydrochloride with not more than 10 ppm, 5 ppm, 3 ppm, 2 ppm, or 1 ppm14-hydroxycodeinone. In other embodiments, oxycodone hydrochloride isprovided with not more than 10 ppm, 5 ppm, 3 ppm, 2 ppm, or 1 ppm14-hydroxycodeinone impurity.

In some embodiments, methods are provided for preparation of crystallineoxycodone hydrochloride (the final product) in order to minimizeresidual impurities including ABUK, oxycodol, and DHC.

The USP acceptance criteria for oxycodone hydrochloride is not more than0.25% 6-α Oxycodol. In some embodiments, methods are provided forpreparation of oxycodone hydrochloride with not more than 0.25%, 0.20%,0.15%, 0.10%, 0.05%, 0.02%, or 0.01% 6-α Oxycodol impurity.

The USP acceptance criteria for oxycodone hydrochloride is not more than0.15% 7,8-dihydro-8β-14-dihydroxycodeinone. In some embodiments, methodsare provided for preparing purified oxycodone hydrochloride with notmore than 0.15%, 0.10%, 0.05%, or 0.01% of an8,14-dihydroxy-7,8-dihydrocodeinone (DHC) impurity.

In some embodiments, methods are provided for conversion of oxycodonebase to oxycodone hydrochloride comprising dissolving the oxycodone basein aqueous acetic acid; followed by treating the oxycodone acetate insolution with ammonium chloride. In some embodiments, one equivalent ofammonium chloride is employed. This method avoids both use of strongacid HCl and use of elevated temperature and thus provides oxycodonehydrochloride with a minimal amount of ABUK impurity.

In some embodiments, methods are provided for conversion of oxycodonebase to oxycodone hydrochloride comprising dissolving or partiallydissolving the oxycodone base in aqueous organic acid, so as to avoidelevated temperature. In some embodiments, methods are provided forconversion of oxycodone base to oxycodone hydrochloride comprisingdissolving the oxycodone base in aqueous organic acid at a temperatureless than 50° C., less than 45° C., less than 40° C., or preferably lessthan 30° C., or at ambient temperature. In some embodiments, methods areprovided for conversion of oxycodone base to oxycodone hydrochloridecomprising dissolving the oxycodone base in aqueous acetic acid at notmore than 50° C., 45° C., 40° C., 30° C., or at ambient temperature.

In some embodiments, methods are provided for conversion of oxycodonebase to oxycodone hydrochloride comprising dissolving or partiallydissolving the oxycodone base in aqueous organic acid, wherein theaqueous organic acid is present in greater than about 1.1, 1.2, 1.3,1.4, 1.5, 2, 3-fold, or more, molar equivalents excess compared to molsof oxycodone base.

In some embodiments, methods are provided for conversion of oxycodonebase to oxycodone hydrochloride comprising dissolving or partiallydissolving the oxycodone base in aqueous organic acid, wherein theaqueous organic acid is present in about 1, or about 0.9, 0.8, 0.7,0.5-fold, or less, molar equivalents compared to mols of oxycodone base.

Surprisingly, it has been found that performing the conversion ofoxycodone base to oxycodone hydrochloride by a method comprisingdissolving oxycodone base in aqueous organic acid at ambienttemperature; followed by treating with hydrochloric acid at ambienttemperature provides oxycodone hydrochloride with not more than 0.01%,0.0075%, 0.005%, 0.001%, 0.0005%, 0.0003%, or 0.0002%14-hydroxycodeinone.

In some embodiments, a method is provided for preparing oxycodonehydrochloride from 14-hydroxycodeinone sulfate, comprising reducing the14-hydroxycodeinone sulfate in the presence of a catalyst to formoxycodone base; dissolving, or partially dissolving, the oxycodone basein an aqueous organic acid to form an oxycodone organic acid salt, andadding hydrochloric acid or ammonium chloride to the oxycodone organicacid salt to form oxycodone hydrochloride, for example, as shown in FIG.6.

In some embodiments, a method is provided for preparation of oxycodonehydrochloride comprising forming oxycodone acetate from oxycodone basein situ, followed by treatment with an aqueous solution of hydrochloricacid or ammonium chloride, for example, as shown in FIG. 7.

In some embodiments, methods are provided for conversion of oxycodonebase to oxycodone hydrochloride in aqueous-acetic acid media that resultin fewer amounts of one or more impurities in the final product,compared to conventional conversion methods. In some embodiments,preparation of oxycodone hydrochloride from purified oxycodone basecomprises mixing purified oxycodone base, water and acetic acid until aclear or almost clear homogenous aqueous oxycodone acetate solution isobtained. In some embodiments, the oxycodone acetate in solution istreated with a small excess (15-20%) of concentrated hydrochloric acidat ambient temperature. The oxycodone hydrochloride crystallizes forabout one hour, and then the crystallizing mixture is diluted with IPAor other organic water miscible solvent (MEK for example) using magneticstirring. The product is filtered off, washed on filter with IPA andacetone, and then dried on filter. The oxycodone hydrochloride productcontains less than 10 ppm of 14-hydroxycodeinone.

In some embodiments, a method is provided for preparation of oxycodonehydrochloride from purified oxycodone base comprising generatingoxycodone acetate in solution and treating with about one equivalent ofammonium chloride at ambient temperature to provide oxycodonehydrochloride.

In some embodiments, a method for preventing or minimizing acidcatalyzed dehydration of DHC to ABUK in the conversion of oxycodone baseto oxycodone hydrochloride is provided. In some embodiments, theoxycodone base is dissolved without heating in acetic acid and water;then HCl or ammonium chloride is added to effect conversion to oxycodonehydrochloride. In some embodiments, an organic solvent is added tocrystallize oxycodone hydrochloride. In some embodiments, the organicsolvent is selected from isopropyl alcohol, ethanol, methanol, acetone,or methyl ethyl ketone. In some embodiments, the conversion step isperformed at a temperature between from about 0° C. to about 50° C.; ata temperature between from about 10° C. to about 40° C.; or at atemperature between from about 15° C. to about 35° C. In someembodiments, the conversion step is performed at ambient temperature.

In some embodiments, crystallization of oxycodone hydrochloride isprovided by addition of water or water and a combination of one or moreorganic water miscible solvents. In some embodiments, the one or moreorganic water miscible solvents are selected from one or more ofisopropyl alcohol, methyl ethyl ketone, and acetone. In someembodiments, crystallization of oxycodone hydrochloride is performed ata temperature between from about 0° C. to about 50° C., between about10° C. to about 40° C.; from about 15° C. to about 35° C.; or at aboutambient temperature.

Examples

Methods are provided for the production of oxycodone hydrochloride withthe goal of minimizing one or more process impurities. The presence andquantification of process impurities in starting materials,intermediates and final product was detected by HPLC and associatedmethods. Generally, reverse phase HPLC was employed for detection andquantification of impurities. Various HPLC methods were employed asdescribed.

In general, samples for injection were dissolved in 0.85% phosphoricacid aqueous solution. Buffer was prepared from sodium dihydrogenphosphate monohydrate (3.45 g in 1000 mL of water). Dodecyl sulfatesodium salt (5.4 g) was added and pH was adjusted with triethylamine topH 7.9. Mobile phase consisted of buffer (730 mL), acetonitrile (150 mL)and methanol (120 mL). The pH of the mobile phase was adjusted to pH 8.5or 9.5 with 25% NaOH. Injection volume was 7 to 50 microliters. HPLC wasrun at 1.0 mL per minute under isocratic conditions with UV monitoringat 220 nm at a column temperature of 45 C. Column Gemini-NX C-18, 150mm×4.6 mm, 5 urn. Runtime was 30 minutes. Use of these conditionsprovided elution order of DHC, ABUK, α-oxycodol, β-oxycodol andoxycodone standards at retention times over 8-25 min.

An HPLC normalization method was an HPLC analysis method based on theassumption that area of all HPLC peaks equal 100%, where the highestoxycodone peak value is in the linear range of 1.00-1.50 units(absorbance units). DHC was evaluated using pH 8.5 mobile phase, ABUKwas evaluated with pH 9.5 mobile phase. The typical sample concentrationwas around 0.3-2.0 mg/mL, and an injection volume was 7 to 50 μL.Generally, the normalization method was employed for the routinepreparative work. Unless otherwise specified, HPLC values providedherein are obtained by the area Normalization method.

An R&D HPLC Assay method for quantification of ABUK was employed basedon determination of HPLC response of exact concentration (amount) from astandard injection (typical standard concentration was 8.24 μg/mL,injection volume—10 μL), and determination of HPLC response of oxycodonesample injection (typical concentration 30-40 mg/mL, injection volume is50 μL) and further proper calculations based on AUC comparison.

An R&D HPLC Assay method for determination of DHC and oxycodol was basedon the assumption that responses (extinction coefficient) of DHC andoxycodol are the same as of ABUK or oxycodone and a direct comparison ofareas of corresponding peaks (ABUK, DHC or oxycodol) was employed.

A QC Method HPLC Assay was employed for quantification of ABUK in asample based on comparison of area ABUK peak of the sample and the sameof sample plus known amount of ABUK standard mixture.

The ABUK R&D Assay method was more sensitive than normalization methodby factor around 450 (considering concentration and volume of injectedanalyte), but the normalization method was employed as more convenientfor the routine preparative work.

Example 1 14-Hydroxycodeinone Sulfate Preparation from Thebaine

14-Hydroxycodeinone sulfate was prepared by oxidation of thebaine asshown in FIG. 2. A 250 mL jacketed reactor was charged with CPS-thebaine(Assay 75.7%; 39.63 g; 96.35 mmol; equivalent to 30.0 g of 100%), NaHSO₄monohydrate (13.57 g, 98.28 mmol), and a solution of DI water (10.25 g)and 97% formic acid (5.26 g, 110.80 mmol).

The mixture was stirred at 20° C. for 15 minutes to provide a brownishto gray easily stirrable mixture. Hydrogen peroxide (30%, 11.8 mL,115.62 mmol) was added to the stirred reaction mixture at 20° C. over 7minutes. After the addition was completed, temperature of the reactionmixture was kept at 20° C. with magnetic stirring for about 15 minutesand then the reaction mixture was heated to 60° C., over a time periodof about 30 minutes. Stirring was continued for 5.75 hours untilcomplete conversion from thebaine into 14-hydroxycodeinone was observedby HPLC, as shown in Table 1. HPLC Normalization Data, was providedusing a 15 cm×4.6 mm Phenomenex NX-C18, 5 μm column.

TABLE 1 Thebaine Oxidation Reaction Progress and Impurity Profile.14-OH-Codeinone Time Event Thebaine (%) (ABUK) (%) DHC (%) 3.50 hours11.83 88.10 ND oxidation 4.20 hours 5.71 94.23 ND oxidation 5.20 hours0.14 99.37 0.0342 oxidation ABUK Sulfate NA 99.89 ND isolated dry ND =not detected.

A precipitation of yellow solids occurred after 2.5 hours of stirring at60° C. The reaction mixture was cooled to 35° C. over a period of 20minutes, and water (50 mL) was added to the crystallizing mixture. Thentemperature was lowered to 30° C. over a period of 20 minutes. Stirringcontinued for 50 minutes at 30° C. till additional crystallizationoccurred. The mixture was cooled further till 20° gradually over onehour, kept at 20° for 0.5 hour and solids were filtered off, washed onfilter with water (2×15 mL). The resultant 14-hydroxycodeinone (ABUK)sulfate yellow solids were dried on filter till constant weight (24.95g, 62.62 mmol, 65% yield, 99.89% purity by HPLC Normalization Method).No starting thebaine and no DHC impurity were detected by HPLCnormalization method as shown in Table 1.

Example 2 Characterization of 14-Hydroxycodeinone Sulfate

To determine molecular formula, 14-Hydroxycodeinone (ABUK) sulfate (LotB) and 14-hydroxycodeinone (ABUK) base (Lot A) were analyzed by HPLC. Asshown in Scheme 3, ABUK sulfate molecular formula was determined to beABUK×0.5H₂SO₄×2H₂O (molecular weight 398.42), as shown in Table 2.

ABUK sulfate and ABUK base samples were analyzed with HPLC. A solutionof each sample of ABUK base and ABUK sulfate was analyzed three times(three injections), HPLC responses were corrected according to KarlFischer water content analysis (10.7% of water in ABUK sulfate sample:9.04% is water in ABUK sulfate crystals and 1.66% is “absorption”water). HPLC data correlate with ABUK×0.5H₂SO₄×2H₂O (molecular weight398.42) as a molecular formula.

TABLE 2 HPLC Analysis for Determination of Molecular Formula. injectionHPLC Lot conc., volume, HPLC Purity, Response per Number ABUK Form mg/gμL Response % μL and conc. Avg. Lot A ABUK Base 0.673 9 98.19 100.0016.21 16.29 MW 313.35 9 98.70 100.00 16.30 9 99.05 100.00 16.35 Lot BABUK 0.832 9 92.90 98.51 12.59 12.58 Sulfate 9 92.74 98.92 12.52 MW398.42 9 93.06 98.45 12.62

Karl Fischer analysis indicated that the ABUK Sulfate sample Lot B had1.66% “absorption” water. So, a response per 4, (volume) andconcentration value (12.58) was multiplied by 1.0166 to obtain 12.79value for the appropriate correction. Ratio of MW's (molecularweights)=398.42/313.35=1.27; ratio of responses 16.29/12.79=1.27. ABUKSulfate molecular formula was thus determined to be ABUK×0.5H₂SO₄×2H₂O(molecular weight 398.42).

HPLC Analysis of the ABUK base (Lot A) confirmed the identity and purity(100%) of the sample as shown in Table 2. HPLC t_(r)=5.926 min.(Normalization method, R&D).

HPLC Analysis of the ABUK sulfate (Lot B) confirmed the identity andpurity (98.51%) of the sample as shown in Table 2. HPLC t_(r)=5.929 min(Normalization Method R&D).

Analysis by proton NMR confirmed the identity of the ABUK base (Lot A),as shown in FIG. 10. ¹H-NMR 300 MHz, (CDCl₃), δ: 6.60-6.70 (m, 3H), 6.20(d, J=10 Hz, 1H), 5.15 (bs, 1H), 4.72 (s, 1H), 3.86 (s, 3H), 3.20 (d,J=18 Hz, 1H), 3.05 (d, J=6 Hz, 1H), 2.37-2.61 (m, 6H), 2.23-2.37 (m,1H), 1.66-1.75 (m, 1H).

Analysis by ¹³C-NMR confirmed identity of the ABUK base (Lot A), asshown in FIG. 11. ¹³C-NMR 75 MHz, (CDCl₃) δ: 194.26, 147.37, 144.41,142.73, 134.70, 130.55, 125.00, 119.56, 115.17, 87.10, 67.81, 64.21,56.89, 46.66, 45.18, 42.59, 29.48, 22.42 ppm.

Example 3 Preparation of 14-Hydroxycodeinone Sulfate from Thebaine withPotassium Hydrogen Sulfate

A 250 mL jacketed reactor was subsequently charged with thebaine (311.37g/mol, 30.0 g, 96.35 mmol), solution of KHSO₄ (14.1 g, 100.44 mmol) inDI water (40 ml) and 97% formic acid (5.2 mL, 133.61 mmol). The mixturewas warmed to 30° C. (Julabo thermostat) and stirred for 20 min to giveyellow to light brown almost homogeneous pale solution. Hydrogenperoxide (30%, 13.5 mL, 119.12 mmol) was added to the stirred reactionmixture at 30-31° C. over 25 minutes. After the addition was completed,temperature of the reaction mixture was kept at 30° C. for 25 minutes,increased to 50° C. with stirring over 10 minutes and kept 9 hours at50-51° C. until the thebaine was completely converted into14-hydroxycodeinone. The precipitation of the yellow solids occurredafter 7 hours stirring at 50° C. Water (10 mL) was added to the reactionmixture and the reaction mixture was cooled down to 20° C. and stirredat this temperature for 14 hours (overnight). The solid material wasfiltered off, washed on filter with icy water (2×20 mL), IPA (2×30 mL)and MTBE (2×40 mL) and dried on filter to provide 14-hydroxycodeinonesulfate (27.81 g, 69.80 mmol, 72.4% yield).

Example 4 Recrystallization of Crude 14-Hydroxycodeinone Sulfate

A 125 mL jacketed reactor, equipped with a mechanical stirrer, wassubsequently charged with 14-hydroxycodeinone sulfate (Lot C, 14.53 g)and water (60 mL). The mixture was heated up to 60° C., hold at thistemperature, cooled down to 30° C., diluted with additional 10 mL ofwater, cooled down to 0° C., hold at 0° C. for 40 minutes. Thetime-temperature profile of the crystallization is shown in the Table 3.

TABLE 3 Time - Temperature Profile of the Recrystallization of ABUKsulfate. Current Time, minutes, temperature, operation Added Notes,Event time (min) Water, mL Stirrer RPM 14- 0.0 (20° C.)- 60 Thecrystallizing hydroxycodeinone 25 (60° C.), mixture is fluid, sulfate,Lot C - 25 min 100 RPM Water Mixing and Heating to 60° C. 60° C. Holding25 (60° C.)- 0.0 The crystallizing 35 (60° C.) mixture is less 10 minfluid, 200 RPM Cooling Down to 35 (60° C.)- 0.0 The crystallizing 30° C.65 (30° C.) mixture is less 30 min fluid, 200 RPM 30° C. Reaction 65(30° C.)- 10 mL The crystallizing Mixture Holding 125 (30° C.) mixturebecame 60 min very thick, 400 RPM Cooling down to 0° C. 125 (30° C.)-N/A The crystallizing 170 (0° C.) mixture was 45 min very thick butstirrable, 300 RPM Holding at 0° C. 170 (0° C.)- N/A The crystallizing210 (0° C.) mixture was 40 min thick but fluid, 300 RPM

The precipitated solids were filtered off, washed on filter with coldacetone-water mixture (3:1, 0° C., 2×30 mL) and with acetone (1×40 mL,to get all material dried) and dried on filter till constant weight. Theprocedure provided ABUK sulfate (11.7 g, 80.5% yield, lot D) with 24 ppmDHC content, as shown in Table 4. The crystallized product ABUK sulfateLot D exhibited diminished DHC impurity to 24 ppm compared to startingcrude ABUK sulfate Lot C with 213 ppm DHC.

TABLE 4 ABUK Sulfate Recrystallization Step Progress by HPLC*.14-OH-Codeinone Time Event (ABUK) DHC Starting ABUK Sulfate dry 99.370.0213 (lot C) Recrystallized ABUK Sulfate dry 99.37 0.0024 (lot D) ABUKSulfate Mother Liquor 98.75 0.1477 *HPLC Normalization Data, %; 15 cm ×4.6 mm Phenomenex NX-C18, 5 μm column) Mobile phase with pH 8.51 wasemployed for the DHC analysis.

Example 5 Purification of 14-Hydroxycodeinone Sulfate by Base Formation

Purification of two combined lots of 14-hydroxycodeinone sulfate wasperformed to eliminate detectable DHC impurity. Two ABUK sulfate lots(lot E, 25.15 g, 170 ppm DHC and lot F; 9.35 g, 161 ppm DHC, totally34.50 g or 86.6 mmol) were combined, mixed with water (360 mL) andtreated with ammonium hydroxide (conc., ˜15 mL) at ambient temperatureuntil the mixture was pH 9.0-9.4 (pH indicator paper). Stirring wascontinued another 0.5 hours and a precipitated ABUK base was filteredoff, washed with water (2×50 mL), dried on filter providing the muddyslurry. Semi-dry slurry was treated with hexanes (˜300 mL) for 2 hoursand filtered off once again, dried on filter providing almost white ABUKbase (32.32 g (wet), MW 313.36, lot G).

The ABUK base (Lot G, 32.32 g (wet) was placed in 500-ml Erlenmeyerflask, mixed with 150 ml of water and 7.0 ml of acetic acid till a clearsolution formed. KHSO₄ (7.06 g) was added over 5 minutes to stirredsolution at ambient temperature till a thick stirrable mixture formed.Stirring was continued for 0.5 hours at ambient temperature and then inan ice bath for 50 minutes. Filtering of the precipitated product,rinsing it with icy water (1×20 ml), MEK (methyl ethyl ketone, 2×50 mL)and drying on filter provided ABUK sulfate, 25.01 g, 72% yield (Lot H).

Both lots of starting ABUK sulfate, intermediate ABUK base and productABUK sulfate were evaluated by HPLC Normalization Data Method, on 15cm×4.6 mm Phenomenex NX-C18, 5 μm column, and are shown in Table 5. NoDHC impurity was detected in the product dry ABUK sulfate by the HPLCnormalization method.

TABLE 5 HPLC Data* for ABUK Sulfate Preparation from ABUK Base.14-OH-Codeinone Time Event (ABUK) DHC ABUK Sulfate 99.98 0.0170 Lot EABUK Sulfate 99.98 0.0161 Lot F ABUK Base dry 99.65 0.0202 Lot G ABUKSulfate 99.86 ND Lot H *HPLC Normalization Data, %; 15 cm × 4.6 mmPhenomonex NX-C18, 5 μm column; ND = not detected.

Example 6 Purification of Combined Lots of ABUK Base by Formation ofABUK Sulfate

14-Hydroxycodeinone (ABUK) base (combined lot, impure, total weight17.32 g, 55.27 mmol) was dissolved in the solution of 5 g acetic acid in60 mL of water at 60° C. Complete dissolution was observed. 70 g ofsaturated solution of Na₂SO₄ was added to the solution of ABUK.Precipitation started after several minutes. The formed slurry wasnaturally cooled to room temperature during 2 hours. Solids werefiltered off, washed with saturated solution Na₂SO₄ (1×30 mL), acetone(2×40 mL) and dried on filter to give 14-hydroxycodeinone sulfate as ayellow/white solid (12.95 g, 58.8% yield) Lot I. No DHC impurity wasdetected in Lot I according to HPLC normalization method.

Example 7 Preparation of ABUK Sulfate from ABUK Base of Mother Liquors

A mixture of ABUK Base Lot J (8.55 g, 27.27 mmol) and ABUK Base lot K,(6.32 g, 20.17 mmol) (totally 47.44 mmol) was made in 250-mL RBF anddissolved in the mixture of water (115 mL and acetic acid (5 mL) atambient temperature. Sodium sulfate (16.15 g) was added portion-wiseover four minutes to the magnetically stirred ABUK acetate solution.Precipitation of the ABUK sulfate as a product occurred in four minutesafter end of addition of sodium sulfate. The crystallizing mixture wasstirred at ambient temperature for two hours and at 5° C. for 0.5 hours.The precipitated product was filtered off, washed on filter with coldwater (2×15 mL) and acetone (2×40 mL) and dried on filter to constantweight 10.05 g, 25.22 mmol, 53% yield of a slightly yellowishcrystalline powder (lot L). The starting ABUK base and product wereevaluated by HPLC Normalization Data, on 15 cm×4.6 mm Phenomenex NX-C18,5 μm column, and are shown in Table 6. No DHC was detected in theproduct dry ABUK sulfate Lot L by the HPLC normalization method as shownin Table 6.

TABLE 6 HPLC Data on ABUK Sulfate Preparation from ABUK Base.14-OH-Codeinone Time Event (ABUK) (%) DHC (%) ABUK Base 98.72 1.2297 LotK ABUK Base dry 98.40 0.6843 Lot J ABUK Sulfate dry 99.65 ND Lot L

Example 8 Preparation of ABUK Sulfate from ABUK Base with Sulfuric Acid

Mixing of dry impure ABUK base (24.96 g, 79.66 mmol), water (112 mL) andacetic acid (3.51 mL) was performed with stirring for 10 min, followedby addition of sulfuric acid (13.27 g, 30%, 40.63 mmol) over 10 min, andmechanical stirring (thick in the beginning and stirrable after 15 minof stirring at 20° C.). The mixture was stirred for 40 min at ambienttemperature, followed by cooling with ice-bath, holding for 40 min,filtering off the product. The product ABUK sulfate was washed withacetone (60 mL, 40 mL), dried on filter. Yield of purified ABUK was28.24 g, 89% (lot M). Evaluation by HPLC revealed ABUK—99.99%,DHC—0.0053%.

Example 9 Preparation of ABUK Solution in Acetic Acid and itsHydrogenation to Form Oxycodone Acetate

Barium diacetate (10.0 g, 39.15 mmol) was dissolved in 10% acetic acidup to 100 mL solution (pH 4.5-5.0). The first crop ABUK sulfate material(27.81 g, 69.80 mmol, containing 34.9 mmol of sulfuric acid) was addedportion-wise to the prepared solution over 15 minutes at 5-10° C. withmagnetic stirring. Stirring was continued for 45 minutes, Celite (3.0 g)was added to the mixture and precipitated material was filtered off on avacuum filter with Celite cake. The filtrate was transferred into 3-neck250-mL RBF, purged with argon, mixed with Pd/C catalyst (0.74 g, 10%,50% LOD) and hydrogen was introduced into the reaction mixture with agas dispersion tube at 5° C. at magnetic stirring. Additional Pd/Ccatalyst (0.84 g) was added after 2 hours of hydrogenation. After 6hours of hydrogenation, formic acid (97%, 10 mL) was introduced into thereaction mixture. The reaction mixture was warmed gradually from 5 to15° C. overnight. Reaction progress was followed by HPLC, as shown inTable 7.

The reaction mixture was purged with argon and stirred with Celite (3 g,15 minutes). Filtering off Pd/C catalyst on filter with Celite cakeprovided almost colorless (yellow tint) solution containing oxycodoneacetate. The reaction progress was followed by HPLC as shown in Table 7.

TABLE 7 Reduction Step Reaction Progress for preparation of Oxycodoneacetate. 14-OH- Codeinone Oxycodol Time Event Oxycodone (ABUK) DHC α/βisomers ABUK Acetate in NA 99.88 ND NA 10% Acetic Acid 1.75 h reduction18.67 80.88 ND ND  3.5 h 98.74 0.1483 ND 0.78/ND  5.75 h 98.88 0.10510.0325 0.84/0.05 After night 98.04 ND 0.0306 0.88/0.25 Oxycodone acetate98.66 ND 0.0420 0.84/0.28 (filtrate) HPLC Data, %; 7.5 cm × 4.6 mmPhenomenex NX-C18, 3 μm column)

Example 10 Preparation of Oxycodone Base as a Dry Solid

Oxycodone acetate solution was diluted with isopropanol (25 mL), cooledto 10° C. and neutralized at 10° C. to 5° C. with ammonium hydroxide(conc., ˜30 mL until pH˜9.5). Stirring continued for 10 minutes andprecipitated solids were filtered off, washed on filter with water (20mL, 2×50 mL, 10 mL) and dried on filter for 0.5 hours. The light graywet material (22.29 g) was prepared. This material was dissolved inchloroform (150 mL), treated with sodium sulfate (anhydrous) for onehour. Solvent was removed in vacuum and gray powder was dried on rotaryevaporator for one hour at 50° C. in the bath, providing oxycodone base(16.31 g, 51.72 mmol, 74.1% yield on ABUK sulfate). Impurity profile isshown in Table 8.

TABLE 8 HPLC Data on Preparation of Oxycodone base from OxycodoneAcetate. 14-OH- Codeinone Oxycodol Time Event Oxycodone (ABUK) DHC α/βisomers Oxycodone acetate 98.62 ND 0.0321 0.88/0.33 (filtrate) OxycodoneBase 99.22 0.0042 0.0280 0.45/0.20 dry *HPLC Data, %; 7.5 cm × 4.6 mmPhenomenex NX-C18, 3 μm column.

Example 11 Preparation of Oxycodone HCl from ABUK Sulfate

A mixture of ABUK sulfate (42.40 g, Lot N) and water (130 mL) was madein a 250-mL 3-neck RBF. The mixture was purged with argon, and Pd/Ccatalyst (2.70 g) was added to stirred mixture at ambient temperature.Reaction progress was monitored by HPLC as shown in Table 9. Thereaction completed in two hours. Formic acid (20 mL) was added to thereaction mixture and the mixture was kept at 50-60° C. for 45 minutesand was allowed to cool to ambient temperature overnight.

Pd/C Catalyst was filtered off and ammonium hydroxide was used for theoxycodone base precipitation (˜60 mL) at temperature less than 15° C.Precipitated product was washed with water (2×75 mL) and dried on filtergiving 28.07 g of oxycodone base. The oxycodone base was transferredinto 250-mL RBF with Pd/C catalyst (0.59 g) and water (120 mL). Formicacid (4.36 mL) was added (pH 2.1) and stirring continued for 45 minutesat 50-60° C. The reaction mixture was cooled to ambient temperature,catalyst was filtered off, and oxycodone base was isolated with ammoniumhydroxide addition to the filtrate at temperature lower than 20° C.Drying on filter provided 29.51 g of the oxycodone base (2^(nd) crude,Lot O).

The oxycodone base (29.51 g, Lot O) was transferred into a 3-neck 250-mLRBF, dissolved in chloroform (˜100 mL). The mixture was heated till thedistillation started and IPA (totally 250 mL) was added portion-wisetill temperature in vapors was stable at 88° C. (1.5 hours). The mixturewas allowed to cool to ambient temperature; solids were filtered, washedon filter with IPA (2×20 mL) and dried on filter to provide purifiedoxycodone base, Lot P, 26.73 g, 84.76 mmol, yield 95% on oxycodone basecrude (28.07 g). The oxycodone base was divided into two portions, andeach portion was converted to oxycodone hydrochloride as described.

The first portion of purified Oxycodone base lot P (13.56 g, 43.0 mmol)was dissolved (in 80-mL beaker over 15 minutes) in a mixture of water(13 mL) and acetic acid (3 mL). Hydrochloric acid (10.41 mol/kg, 5.0 g,or 51.6 mmol) was added to the solution over 5 minutes. Stirring wascontinued for another 40 minutes and IPA (55 mL) was added over 15minutes. Stirring was continued for another 30 minutes. Precipitatedproduct was filtered off, washed on filter with IPA (2×20 ml) andacetone (2×20 mL), dried on filter providing 14.74 g oxycodone HCl(39.86 mmol, 93% yield on OC base purified) lot Q.

The second portion of purified oxycodone base lot P (13.00 g, 41.22mmol) was dissolved (in 80-mL beaker over 10 minutes) in a mixture ofwater (17 mL) and acetic acid (2.80 mL). Ammonium chloride (MW 53.49,2.20 g or 41.22 mmol) was added to the stirred solution over 20 minutes.Stirring was continued for another two hours at ambient temperature andthen the crystallizing solution was cooled down to +5° C. (ice bath).Stirring was continued for one hour and precipitated product wasfiltered off, washed with cold ethanol (2×7 mL), IPA (15 mL) and acetone(20 mL). Drying on filter provided 10.88 g of oxycodone HCl, Lot R(29.42 mmol, 71% yield on oxycodone base purified).

TABLE 9 HPLC Data on Reduction and Oxycodone (OC) HCl Preparation.14-OH- Codeinone Time Event Oxycodone (ABUK) DHC Oxycodol ABUK sulfateNA 99.99   0.0067 NA (lot N) 2 hours of 98.29 0.0247 0.0289 1.50/0.09hydrogenation After 50° C. 98.20 0.0440 ND 1.53/0.16 Heat and Cool Afterformic acid 98.85 0.0765 0.0102 0.53/0.14 2^(nd) Reduction (reactionmixture) OC base 2 (isolated, 99.03 ND ND 0.45/0.20 Lot O) OC baseisolated 99.57 0.0022 0.0057 0.23/0.18 IPA purified, Lot P ⁽¹⁾ OC HClcrystalline 99.96 ND ND 0.0166/ND    Lot Q OC HCl crystalline 99.99 NDND 0.0130 Lot R Note: Area normalization method, HPLC Data, %; 15 cm ×4.6 mm Phenomenex NX-C18, 5 μm column)

The following HPLC methods were employed for ABUK determination in Lot Qand Lot R Oxycodone HCl Samples (R&D Assay method). A 1 ml/min flow ratewas employed.

1. Averaged response of 8.24 mg/ml external standard (pure oxycodonebase solution in 0.85% phosphoric acid, two 10 μl-injections):

(717.0+731.3)/2=724.15.

2. Sample preparation was performed by dissolution of 76.3 mg of Lot Qsample in 2.25 g of 0.85% phosphoric acid for a sample concentration76.3 mg/2.25 mL=33.91 mg/ml or 0.03391 g/ml. Sample preparation wasperformed by dissolution of 65.3 mg of Lot R sample in 2.02 g of 0.85%phosphoric acid) for a sample concentration 65.3 mg/2.02 mL=32.33 mg/mlor 0.03233 g/ml.

3. The Response of 50 mkl Lot Q sample injection: 48.3; and response of50 μl Lot R sample injection: 21.8

4. Calculation of ABUK content was calculated as follows:ppm=Rsmpl/Rstd×Cstd (mkg/ml)/Csmpl (g/mL)×1/1.715×1/5×0.85; where 1/5 isadjusting factor for injection volumes; 0.85 is adjusting factor ofoxycodone base and oxycodone HCl hydrate according to their molecularweights (315.36/369.84=0.85); 1/1.715 is adjusting factor for RRF(relative response factor, ABUK has conjugated double bonds and itsabsorbance is higher than absorbance of oxycodone, DHC or oxycodol).

The amount of Sample Lot Q ABUK content was determined as=48.3/724.15×8.24/0.03391×1/1.715×1/5×0.85=1.61 ppm. Indirect ABUKdetermination (oxycodol as a reference) gave 1.73 ppm number: (48.3(ABUK area)/2700.9 (oxycodol area)=0.0178; and 0.0178*0.0166%/1.71(RRF)=1.73 ppm.

The amount of Sample Lot R ABUK content was determined as=21.8/724.15×8.24/0.03233×1/1.715×1/5×0.85=0.76 ppm. Indirect ABUKdetermination (oxycodol as a reference) gave 0.87 ppm number: (21.8(ABUK area)/1903 (oxycodol area)=0.01146; 0.01146*0.0130%/1.71(RRF)=0.87 ppm.

Therefore, methods are provided for preparation of oxycodonehydrochloride from 14-hydroxycodeinone sulfate that provide oxycodonehydrochloride with less than 10 ppm, less than 5 ppm, less than 2 ppm,or less than 1 ppm, of 14-hydroxycodeinone (ABUK) in the final product.

Example 12 Oxycodone HCl Preparation and Crystallization

Purified oxycodone base (19.22 g, 60.95 mmol, Lot S) and a mixture ofwater (28.83 g) and acetic acid (2.82 g, 16.19 mmol/g, 44.70 mmol) werecharged into 150-mL RBF, equipped with mechanical stirrer. Stirring ofthe mixture at ambient temperature (230 RPM) resulted in a thinsuspension formation. Hydrochloric acid (6.94 g, 10.094 mmol/g, 70.09mmol) was added portion-wise over 45 minutes: at the beginning—about2.30 g (over ˜4 minutes, the mixture became transparent, followed by aprecipitation); the rest of the hydrochloric acid was added portion-wise(5 drops at once) over 40 minutes (rate of stirring was increase to 250RPM after 30 minutes). The mixture was stirred for 0.5 hours at ambienttemperature, 0.5 hours at ice-bath temperature, and cold IPA (0° C., 77mL) was added over 25 minutes. Stirring continued for 0.5 hours, and theprecipitated product was filtered off. It was washed with IPA (2×40 mL)and acetone (2×40 mL), dried on filter providing 21.73 g (58.76 mmol,96.4% yield) of oxycodone HCl crystalline white solids, Lot T. Impurityprofiles of materials of interest were monitored by HPLC, normalizationmethod, as shown in Table 10.

TABLE 10 HPLC* Profile of Oxycodone (OC) base, OC HCl and its MotherLiquor (ML). Oxycodol Sample DHC α/β isomers ABUK Oxycodone OC Purified0.0320  0.10/ND 0.0023 99.73 Lot S (pH 8.5) OC HCl ND    ND/ND ND 99.79Lot T (pH 8.5) (6 ppm, QC Assay method) OC HCl 0.2155 0.6535/ND ND 98.66Lot T -ML (pH 8.5) *normalization method, %, HPLC Mobile Phase pH 9.50,except DHC determination, ML = mother liquor

As shown in Table 10, this method for conversion of oxycodone base tooxycodone hydrochloride does not promote acid catalyzed dehydration ofDHC impurity to 14-hydroxycodeinone (ABUK); but rather the DHC remainsin the mother liquor. In addition, this method provides oxycodonehydrochloride with not more than 10 ppm 14-hydroxycodeinone.

Therefore, by a method comprising at least partially dissolvingoxycodone base in acetic acid and water and converting to oxycodonehydrochloride with hydrochloric acid at ambient temperature, oxycodonehydrochloride was provided without detectable 14-hydroxycodeinone (ABUK)by the HPLC normalization method, and with not more than 10 ppm14-hydroxycodeinone level by QC Assay method.

Example 13 Preparation of Oxycodone HCl from 14-Hydroxycodeinone Sulfate

Oxycodone hydrochloride was prepared from 14-hydroxycodeinone sulfate asshown in FIG. 5. A mixture of ABUK hemisulfate dihydrate (20.0 g, Lot Ulot, 50.20 mmol) and water (65 mL) was made in a 250-mL 3-neck RBF. Thismixture was purged with argon and Pd/C catalyst (0.65 g, 10%, 50% LOD)was loaded into the flask. Hydrogen gas purged into the flask at ambienttemperature for 5.25 hours and HPLC analysis indicated almost the end ofreaction. Formic acid (5 mL) and a fresh portion of Pd/C catalyst (0.37g) were added to the reaction mixture and the reaction mixture washeated at 50° to 60° C. for 45 minutes and cooled naturally till ambienttemperature.

Pd/C catalyst was filtered off on filter with Celite cake, flask andcake were rinsed with acetic acid (5%, 15 mL) and water (2×20 mL).Oxycodone base was isolated using ammonium hydroxide (conc., ˜35 mL) byneutralization of the acids in the filtrate till pH˜9.5 at 5-10° C.Oxycodone base was washed with water (3×40 mL) and dried on filterproviding 12.57 g of dry oxycodone base crude, Lot V. This amount ofoxycodone base crude was dissolved in chloroform (˜50 mL, 250-ml 3-neckRBF), this solution was heated to boiling point and IPA (250 mL) wasadded gradually over 1 hour at boiling point of the mixture and then 150mL of the solvent was distilled (at 58-82° C.). The mixture was cooleddown gradually to ambient temperature, the precipitated oxycodone basewas filtered off, washed with IPA (cold, 2×15 mL) and dried on filterproviding 11.92 g (37.80 mmol) of purified oxycodone base, Lot W (95%yield). Total yield on ABUK sulfate was 75%. Impurity profile is shownin Table 11.

TABLE 11 HPLC Data on ABUK Reduction and Oxycodone Base Preparation.14-OH- Codeinone Oxycodol Time Event Oxycodone (ABUK) DHC α/β isomersABUK (lot U) NA 99.99   0.0063 NA 5.25 hours 95.52 0.0279 0.02101.38/0.08 hydrogenation After hydrogenation 95.31 0.0185 0.00651.45/0.27 at 50° with FA OC Filtrate as 95.17 0.0024 0.0119 1.50/0.30Formate-Acetate Salts OC Base Crude, lot V 98.31 ND 0.0085 0.66/0.16 OCBase IPA treated, 99.77 0.0119 0.0109 0.04/0.03 Lot W FA—Formic Acid,HPLC Data, %; 15 cm × 4.6 mm Phenomenex NX-C18, 5 μm column.

Example 14 Reduction of ABUK Sulfate with Formic Acid Over Pd/C Catalyst

ABUK sulfate (12.03 g, 30.19 mmol, Lot X) was slurred in 48 mL of water(initial pH was 2.61). Pd/C catalyst (0.3 g, 10%, 50% LOD) was added tothe slurry, then 0.2 ml of formic acid was added to the slurry to adjustto pH 1.34. Reaction was monitored according to pH of the reactionmixture, time and amount of added formic acid as shown in Table 12.

TABLE 12 Reduction of ABUK Sulfate with Formic Acid (FA). pH before pHafter Time, h FA addition Comments FA addition 0.00 2.61 0.2 mL formicacid added 1.34 to reaction mixture 0.50 4.23 0.2 mL formic acid added1.21 to reaction mixture 1.00 4.44 0.3 mL formic acid added 1.32 toreaction mixture 1.75 4.75 0.5 mL formic acid added 1.32 to reactionmixture 4.00 h 2.32 0.2 mL formic acid added 1.64 to reaction mixture4.50 h NA Reaction was stopped NA

The catalyst was filtered off, washed with water (2×10 mL), pH of thefiltrate was adjusted to 9, using ammonium hydroxide conc. aqueoussolution. After one hour stirring, the product was filtered off, washedwith water (2×20 mL) and dried on the filter to constant weight to giveoxycodone free base as white powder—8.8 g. (92.4% yield), lot Y.

Example 15 Oxycodone Hydrochloride Preparation and Crystallization

As described above, oxycodone base purified (Lot P, 13.56 g, 43.0 mmol)was dissolved (in 80-mL beaker over 15 minutes) in the mixture of water(13 mL) and acetic acid (3.0 mL) at ambient temperature. Hydrochloricacid (10.41 mol/kg, 5.0 g or 51.6 mmol) was added to the solution over 5minutes. Stirring was continued for another 40 minutes and IPA (55 mL)was added over 15 minutes. Stirring was continued for another 30minutes. Precipitated product was filtered off, washed on filter withIPA (2×20 ml) and acetone (2×20 mL), dried on filter providing 14.74 goxycodone HCl (39.86 mmol or 93% yield on OC base purified)—lot Q.

The HPLC profile of the final product oxycodone hydrochloride, Lot Q,and the starting material, oxycodone base, Lot P, are shown in Table 13.Two special oxycodone hydrochloride Lot Q HPLC analyses were performedusing R&D and QC Assay methods. Oxycodone HCl Lot Q exhibited14-hydroxycodeinone impurity by HPLC R&D laboratory method of 1.61 ppm,and QC laboratory method of 3.0 ppm.

TABLE 13 HPLC Normalization Analysis of Lot Q Oxycodone HCl and ItsPrecursor. 14-OH- Codeinone Oxycodol Time Event Oxycodone (ABUK) DHC α/βisomers OC base isolated 99.57 0.0022 0.0057    0.23/0.18 IPA purifiedLot P OC HCl crystalline, 99.96 ND ND 0.0166/ND Lot Q

Example 16 Evaluation of Oxycodone Hydrochloride with Improved ImpurityProfile

Oxycodone hydrochloride was prepared from oxycodone base purified by (a)dissolution of oxycodone as its acetate salt in water, by (b) conversionof the oxycodone acetate salt into its hydrochloric acid salt at ambienttemperature by using either hydrochloric acid or ammonium chloride, asindicated, and by (c) crystallization of oxycodone hydrochloride asprovided herein, as noted in Table 14. As used herein “PF” is used todenote purification factor (in parenthesis) which refers to ratio ofimpurity content before and after preparation, purification and/orcrystallization. “ND” refers to not detected. “NA” means not applicable.

TABLE 14 Impurity Profile for Conversion of Oxycodone Base to OxycodoneHydrochloride by Acetic Acid Method or by Ammonium Chloride Method.Oxycodol ABUK, DHC, (major HPLC ppm ppm isomer), Method, Substance OC, %(PF) (PF) % (PF) Notes OC Base Crude 98.31 ND 85 0.6600 NormalizationLot Z OC Base IPA 99.70 119 109 0.0400 Normalization Purified Lot AA(IPA + chloroform) OC HCl NA 6.10 3.84 0.0103 R&D, Assay Lot BB (19.51)(28.39) (3.88) Method (HCl method) NA 2 NA NA QC, Assay (59.5) Method OCBase Crude 98.55 ND 47 1.0400 Normalization Lot CC OC Base IPA 99.86 ND89 0.0800 Normalization Purified Lot DD (IPA + chloroform + MeOH) OC HCl99.96 ND ND 0.0037 Normalization Lot EE (2.16) (ammonium NA 0.27 2.640.0165 R&D, Assay chloride (33.71) (4.85) Method method) NA 2 NA NA QC,Assay Method OC Base Crude 99.03 ND ND 0.4500 Normalization Lot O OCBase IPA 99.57 22 57 0.2390 Normalization Purified Lot P (IPA +chloroform) OC HCl NA 1.61 6.53 0.0090 R&D, Assay Lot Q (13.66) (8.73)(26.56) Method NA 3 NA NA QC, Assay (7.33) Method OC HCl NA 0.76 2.330.0066 R&D, Assay Lot R (28.95) (24.46) (36.21) Method (ammonium NA 4 NANA QC, Assay chloride (5.5) Method method)

Each of the oxycodone hydrochloride samples in Table 14 exhibits anImpurity Profile for oxycodone hydrochloride samples with not more than10 ppm, or not more than 5 ppm, or not more than 3 ppm, or not more than2 ppm, or not more than 1 ppm 14-hydroxycodeinone.

Each of the oxycodone hydrochloride samples in Table 14 exhibits anImpurity Profile for oxycodone hydrochloride samples with not more than0.02%, 0.015%, or 0.01% 6-oxycodol, major isomer.

Each of the oxycodone hydrochloride samples in Table 14 exhibits anImpurity Profile for oxycodone hydrochloride samples with not more than10 ppm, or not more than 5 ppm DHC.

In case of oxycodone hydrochloride sample Lot BB, as a result ofoxycodone hydrochloride preparation and its crystallization at ambienttemperature, ABUK impurity was present at only 6.10 ppm, (R&D HPLC assaymethod). Oxycodone hydrochloride sample Lot BB impurity oxycodol majorisomer was present at 0.0103%, and DHC was present at 3.84 ppm (R&D HPLCassay method).

In case of oxycodone hydrochloride Lot EE, prepared via the ammoniumhydrochloride method and crystallization at ambient temperature, ABUKwas present at only 0.27 ppm (R&D HPLC assay method). Lot EE oxycodonehydrochloride also exhibited a reduced impurity profile for DHC andoxycodol impurities with 2.64 ppm DHC impurity, and 0.0165% oxycodol,major isomer (R&D HPLC assay method).

In case of Lot Q oxycodone hydrochloride sample, as a result ofoxycodone hydrochloride preparation with hydrochloric acid andcrystallization at ambient temperature, ABUK was present at only 1.61ppm (R&D HPLC assay method). Lot Q oxycodone hydrochloride alsoexhibited 6.53 ppm DHC, and 0.009% oxycodol (R&D HPLC assay method).

In case of Lot R oxycodone hydrochloride prepared by ammonium chloridemethod, and as a result of oxycodone hydrochloride preparation andcrystallization at ambient temperature, ABUK was present at only 0.76ppm (R&D HPLC assay method). Lot R Oxycodone hydrochloride Lot R alsohad minimal DHC and oxycodol impurities of DHC 2.33 ppm, and 0.0066%oxycodol (R&D HPLC assay method).

Example 17 Oxycodone Crude Purification

Oxycodone base crude Lot FF (21.76 g) was charged into 250-mL one-neckRBF with propylene glycol (38 mL), water (76 mL) and IPA (25 mL)mixture. The mixture was heated at reflux for 2 hours (115-133° C. inthe bath), cooled down to ambient temperature over 30 minutes and keptin the ice bath for 0.5 hours. The precipitated product was filteredoff, washed with water twice (30 and 15 mL) and dried on filter tillconstant weight (20.96 g or 96.3% yield, Lot GG). Starting material andproduct was evaluated by HPLC as shown in Table 15. Data, %; 15 cm×4.6mm Phenomenex NX-C18, 5 μm column). Purification of crude oxycodone baseby use of propylene glycol and IPA significantly reduced DHC andoxycodol impurities in the purified oxycodone base.

TABLE 15 HPLC Data on Oxycodone Base Purification. 14-OH- CodeinoneOxycodol Time Event Oxycodone (ABUK) DHC α/β isomers OC Crude, Lot FF97.85 ND 0.0482 0.98/0.36 OC Base Purified, 99.48 ND 0.0129 0.31/0.14Lot GG (HPLC Data, %; 15 cm × 4.6 mm Phenomenex NX-C18, 5 μm column)

Example 18 Oxycodone Crude Purification

Oxycodone base crude (31.23 g, Lot FF) was charged into 500-mL one-neckRBF with IPA (20 mL), water (114 mL) and methoxyethanol (57 mL) mixture.The mixture was heated at reflux for 4.5 hours (110-115° in the bath),cooled down to ambient temperature over 30 minutes and kept in the icebath for 0.5 hours. The precipitated product was filtered off, washedwith water (50 mL and 30 mL) and dried on filter till constant weight(29.83 g or 95.5% yield, Lot II). Impurity profiles are shown in Table16.

TABLE 16 HPLC Data on Oxycodone Base Purification. 14-OH- CodeinoneOxycodol Time Event Oxycodone (ABUK) DHC α/βisomers OC Grade, Lot FF97.95 ND 0.0482 0.98/0.36 OC Base, Lot II 99.65 0.0062 0.0133 0.25/0.12

The methods provided herein for oxycodone hydrochloride preparation andcrystallization at ambient temperature using aqueous acetic acid as amedia for the oxycodone hydrochloride preparation, or generation ofoxycodone acetate prior to introduction of HCl or ammonium chloride, andvarious crystallization techniques are employed to minimize DHC, ABUKand oxycodol impurity content in the final finished product.

Example 19 14-Hydroxycodeinone Sulfate Preparation and Crystallization

In this experiment, thebaine is converted to ABUK sulfate andcrystallized with product washing on filter with 40% ammonium sulfateaqueous solution ((NH₄)₂SO₄) in order to prevent product losses due toits high solubility in water or aqueous organic solvents, such asacetone/water mixtures.

A 250 mL jacketed reactor was subsequently charged with thebaine (lotTCPS-132, Lot LL, 79% Assay Thebaine—37.97 g, MW 311.37 g/mol; 96.35mmol, 1 equivalent), solution of DI water (8.03 g) and 97% formic acid(5.72 g, 120.54 mmol, 1.25 equiv) and then sodium hydrogen sulfate(13.57 g, 98.28 mmol, 1.02 equiv. to thebaine). The mixture was stirred(125 RPM) at 20° C. for 5 minutes to give a good stirrable mixture.Hydrogen peroxide (30%, 13.64 g, 1.25 equiv. to thebaine) was added tothe stirred reaction mixture at 20° C. over two minutes. After alladditions were completed, the temperature of the reaction mixture was30° C. The reaction temperature (70° C.) was reached after 8 minutes ofheating with Julabo (set to 72° C.). Stirring was continued for 110minutes until the complete thebaine conversion into 14-hydroxycodeinone.Complete dissolution and a clear reaction mixture were observed after 7minutes of heating at 70° C. The precipitation of yellow solids occurredafter 50 minutes of stirring at 70° C. (after seeding by scratching theflask wall). The reaction mixture was cooled down to 25° C. over aperiod of 52 minutes. Water (50 mL) was added to the crystallizingmixture in two portions: 50 mL at 30° C. (stirrer was set for 250 RPM)and another 50 mL portion at 25° C. Stirring at 25° C. was continued for30 minutes until additional product crystallization occurred. Thecrystallizing mixture was cooled down to 0° C. and kept at 0° C. for 30minutes. See cooling crystallization profile in Table 17. Theprecipitated product was filtered off, washed on filter with cold 40%ammonium sulfate aqueous solution. Drying on filter provided 30.08 g ofyellow powder of ABUK sulfate (ABUK×0.5H₂SO₄×2H₂O, MW 398.42, 75.50 mmolor 78.4% yield, lot MM).

TABLE 17 Time - Temperature Cooling Profile for Crystallization of14-hydroxycodeinone sulfate. Current Time, minutes, (temperature),operation Added Water, Notes, Event time (min) mL Stirrer RPM End ofReaction 0.00 (70° C.) 0.0 The crystallizing mixture is fluid, 125 RPMCooling and 0.0 (70° C.)- 50 mL at The crystallizing stirring 52 (25°C.) 30° C. and mixture is fluid, 52 min 50 mL at 125 RPM and 250 25° C.RPM after water addition 25° C. Reaction 52 (30° C.)- NA Thecrystallizing Mixture Stirring 82(30° C.) mixture is fluid, 30 min 250RPM 25° C. to 0° C. 82 (25° C.)- NA The crystallizing Reaction 127 (0°C.) mixture is fluid, Mixture Cooling 45 min 250 RPM Stirring at 0° C.127 (0° C.)- NA The crystallizing 157 (0° C.) mixture is fluid, 30 min250 RPM

Example 20 Oxycodone Base Preparation to Minimize Oxycodol Formation

ABUK sulfate (30.03 g or 75.50 mmol, lot MM, 020-140-149) and water (135mL) were charged into 3-neck 500-mL RBF. The mixture was stirredmagnetically with argon gas purging for about 10 minutes (gas-dispersiontube, moderate gas flow, magnetic stirrer) at around 40° C. Pd/Ccatalyst (0.90 g, 10% Pd/C, LOD 50%) was mixed with water (20 mL) andtransferred into the flask. Hydrogen gas was introduced into theheterogeneous mixture in the flask at 38-42° C. for 140 minutes. Thereaction mixture was cooled down to ambient temperature, catalyst wasfiltered off and washed with water (˜3×30 mL). Oxycodone crude base wasisolated by precipitation with concentrated aqueous solution of ammoniumhydroxide (˜9 mL) until pH˜9.2-9.5 at 20-22° C. (mechanical stirring,250 RPM). The precipitate was washed with water (1×50 mL, 1×25 mL) anddried on filter till constant weight. The procedure provided oxycodonebase crude: 19.74 g (62.60 mmol or 82.9% yield on ABUK sulfate; lot NN).

In this experiment, ABUK sulfate is reduced to oxycodone base crudeproduct in an aqueous system at 38-42° C. without acetic acid. Themethod preserved optimal activity of Pd/C catalyst and a high rate ofreduction was accompanied by a somewhat lower oxycodol by-productformation (1.16% in the reaction mixture instead 1.25-1.60% with aceticacid co-solvent), as shown in Table 18.

TABLE 18 HPLC Data on ABUK Sulfate Reduction and Oxycodone BasePreparation 14-OH- Codeinone Oxycodol Time Event Oxycodone (ABUK) DHCα/β isomers 60 min hydrogenation 38.32 60.48 ND 0.82/ND  120 minhydrogenation 98.59 ND ND 1.41/ND  filtrate 97.57 19 ppm 0.05741.16/0.13 OC base Crude, 98.29 34 ppm 0.0553 0.67/0.05 Lot NN (HPLCData, %; 15 cm × 4.6 mm Phenomenex NX-C18, 5 μm column)

1-7. (canceled)
 8. Isolated 14-hydroxycodeinone sulfate or a hydratethereof.
 9. (canceled)
 10. The isolated 14-hydroxycodeinone sulfate orhydrate thereof according to claim 8 that is a 14-hydroxycodeinonehemisulfate or a hydrate thereof.
 11. The isolated 14-hydroxycodeinonesulfate hydrate of according to claim 8 selected from a14-hydroxycodeinone sulfate hemihydrate, monohydrate, sesquihydrate ordihydrate.
 12. The isolated 14-hydroxycodeinone sulfate or hydratethereof according to claim 8 having not more than 0.05% total8,14-dihydroxy-7,8-dihydrocodeinone (DHC) impurity.
 13. The isolated14-hydroxycodeinone sulfate or hydrate thereof according to claim 12having less than 0.01% of an 8,14-dihydroxy-7,8-dihydrocodeinone (DHC)impurity. 14-22. (canceled)
 23. The isolated 14-hydroxycodeinonehemisulfate or hydrate thereof according to claim 10 that is a14-hydroxycodeinone hemisulfate monohydrate, or a 14-hydroxycodeinonehemisulfate dihydrate.
 24. The isolated 14-hydroxycodeinone hemisulfatehydrate according to claim 10 that is a 14-hydroxycodeinone hemisulfatedihydrate.
 25. The isolated 14-hydroxycodeinone hemisulfate dihydrateaccording to claim 24 having less than 300 ppm of an8,14-dihydroxy-7,8-dihydrocodeinone (DHC) impurity.
 26. The isolated14-hydroxycodeinone hemisulfate dihydrate according to claim 25 havingless than 150 ppm of an 8,14-dihydroxy-7,8-dihydrocodeinone (DHC)impurity.
 27. The isolated 14-hydroxycodeinone hemisulfate dihydrateaccording to claim 26 having less than 100 ppm of an8,14-dihydroxy-7,8-dihydrocodeinone (DHC) impurity.
 28. The isolated14-hydroxycodeinone hemisulfate dihydrate according to claim 27 havingless than 75 ppm of an 8,14-dihydroxy-7,8-dihydrocodeinone (DHC)impurity.
 29. The isolated 14-hydroxycodeinone hemisulfate dihydrateaccording to claim 28 having less than 50 ppm of an8,14-dihydroxy-7,8-dihydrocodeinone (DHC) impurity.
 30. The isolated14-hydroxycodeinone hemisulfate dihydrate according to claim 29 havingless than 25 ppm of an 8,14-dihydroxy-7,8-dihydrocodeinone (DHC)impurity.
 31. The isolated 14-hydroxycodeinone sulfate or hydratethereof according to claim 8 obtained by exposing thebaine to hydrogenperoxide or peroxyacid and another organic acid in the presence ofsodium hydrogen sulfate, sodium sulfate, potassium sulfate, and/orpotassium hydrogen sulfate in an aqueous reaction mixture.
 32. Theisolated 14-hydroxycodeinone sulfate or hydrate thereof according toclaim 31, wherein the another organic acid is formic acid.
 33. Theisolated 14-hydroxycodeinone sulfate or hydrate thereof according toclaim 31, having less than 300 ppm of any8,14-dihydroxy-7,8-dihydrocodeinone (DHC) impurity.
 34. The isolated14-hydroxycodeinone sulfate or hydrate thereof according to claim 31,having less than 150 ppm of any 8,14-dihydroxy-7,8-dihydrocodeinone(DHC) impurity.
 35. The isolated 14-hydroxycodeinone hemisulfatedihydrate according to claim 31, having less than 100 ppm of any8,14-dihydroxy-7,8-dihydrocodeinone (DHC) impurity.
 36. The isolated14-hydroxycodeinone hemisulfate dihydrate according to claim 31, havingless than 50 ppm of any 8,14-dihydroxy-7,8-dihydrocodeinone (DHC)impurity.
 37. The isolated 14-hydroxycodeinone hemisulfate dihydrateaccording to claim 31, having less than 25 ppm of any8,14-dihydroxy-7,8-dihydrocodeinone (DHC) impurity.